1. Field of the Invention
The invention is generally related to priming macrophages for enhanced killing potential. More particularly, the invention includes administering a priming factor to a patient so that the macrophages in the patient will be primed for enhanced killing activity a certain number of days after the priming factor was administered.
2. Description of the Prior Art
It is now well understood that phagocytes, such as alveolar macrophages and the like, play an important role in controlling microbial infections. Baboir, New Eng. J. Med., 298:659-68 (1978), has explained that upon encountering a foreign material, such as an invading bacterial cell, phagocytes produce a respiratory burst wherein highly oxidative species, such as superoxide anion (O.sub.2.sup.-), singlet oxygen (O.sub.2), and hydrogen peroxide (H.sub.2 O.sub.2), are produced. The purpose of the respiratory burst is to provide a battery of oxidizing agents that can be used by the phagocyte for the destruction of invading micro-organisms and other foreign material. Many agents, both particulate and soluble, are able to activate the respiratory burst. Particulate activating agents include opsonized bacteria, zymosan (a preparation of yeast cell walls), and latex spheres. Among the soluble activating agents are phorbol myristate acetate, a complex plant product; a variety of ionophores; the complement C5a; and fluoride ion. Activation may not require phagocytosis; rather, simply contact of the foreign stimulant with the phagocyte surface may be enough to activate the phagocyte to produce the respiratory burst. The oxygen-dependent cytotoxic mechanisms of phagocytes are discussed at length in Klebanoff, Adv. Host Def. Mech., (Vol. 1, eds. J. Gallin and A. Fauci, Raven Press, New York 1982 pp.111-163).
Baboir also explains that the respiratory burst activity can be detected by monitoring the chemiluminescence phenomena wherein light emission accompanies activation of the phagocyte. The light emission stems from the oxidative species produced by the phagocyte. For example, singlet oxygen is an electronically excited state of oxygen that can revert spontaneously to atmospheric oxygen, and this reversion is accompanied by a pulse of light. However, it is now generally believed that superoxide anion is responsible for the chemiluminescent response.
Many researcher groups have used chemiluminescence to study macrophage activity. For example, Donaldson et al., Br. J. exp. Path., 65:81-90 (1984), used chemiluminescence measurements to show that macrophages treated with chrysotile asbestos and Cornyebacterium parvum elicited greater levels of reactive oxygen species than saline treated macrophages. In addition, Donaldson showed that peritoneal exudate cells harvested from CF.sub.I mice five days after injection with chrysotile asbestos or C. parvum had a approximately a two to three fold increase in measured chemiluminescence. Donaldson et al. suggest that the asbestos-activated macrophages are primed to produce increased amounts of reactive oxygen species which could be triggered by a number of inhalable particles (e.g., bacteria, yeast, pollen, and asbestos itself), and that an excess of these reactive oxygen species in the alveolar spaces leads to epithelial damage and ultimately to fibrosis. Other examples where chemiluminescent response measurements were used include: Chida et al., Infect. Immun., 55:1476-1483 (1987), reports on a study where infant and mature rabbits were vaccinated with the heat killed Bacillus Calmette Guerin (BCG) strain of Myobacterium bovis and shows that the alveolar macrophages (AM) of infant rabbits were poor responders to phorbol myristate acetate (PMA)-induced chemiluminescent responses compared to AM from older rabbits which were vaccinated with BCG, thus illustrating a deficiency in the AM of neonatal and infant animals that may account for their increased susceptibility to pulmonary infections; Hayakawa et al., J. Leuk. Biol., 45:231- 238 (1989), reports on a study where a chemiluminescent assay was used to show that AM from BCG vaccinated rabbits (3 weeks after i.v. injection), when cultured in vitro with various serum preparations, could result in significant changes in the chemiluminescent (CL) response; Myrvik et al., J. Invest. Surg., 2:381-389 (1989), reports on a study where extracellular slime from Staphyloccocus epidermis was found to affect the CL response on PMA-induced rabbit AM; Umehara et al., Cell. Immun., 119:67-72 (1989), reports on a study where CL responses were used to show L-Fucose blocks migration inhibition factor (MIF)/macrophage activation factor (MAF) priming of rabbit AM (PMA-induced oxidative response used); Giridhar et al., J. Leuk. Biol., 49:442-448 (1991), reports on a study where CL responses were used to show priming of rabbit AM by herpes simplex virus type 2 infection.
There has been much effort made in finding materials which can provide protection from infection. U.S. Pat. Nos. 4,707,471 and 4,795,745 to Larm et al. disclose that pretreatment with water soluble aminated .beta.-1,3-D-glucans can stimulate the activity of macrophages such that animals are protected from virulent pneumococci. U.S. Pat. No. 5,045,320 to Mescher discloses that immunization with a solid support having a variety of different ligands attached can elicit and augment T cell mediated responses U.S. Pat. No. 4,900,722 to Williams et al. discloses a class of phosphorylated glucans useful in the treatment of infections. U.S. Pat. No. 5,078,996 to Conlon et al. discloses the use of granulocyte stimulating factor to activate macrophage tumoricidal activity U.S. Pat. No. 3,119,741 discloses an acylated bacterial lipopolysaccharide useful as a non-specific immunological agent.
There is a need for a short-term, non-specific therapeutic which provides protection against a wide variety of bacterial and viral infections. Such a therapeutic could ideally be used in anticipation of events which lead to infections such as surgery, biological warfare, natural disasters and the like. Up-regulation of the macrophage oxidative killing potential could be beneficial to such an end; however, the time duration for such priming would advantageously be limited so as to avoid cellular and matrix protein damage, fibrosis, and other injuries which would occur from the chronic production of reactive oxygen species.